Proposed is an application in response to PA-09-020, International Research Collaboration on Drug Addiction. that brings together Johns Hopkins University and the YR Gaitonde Centre for AIDS Research and Education to characterize interactions between HIV, hepatitis C virus (HCV), tuberculosis (TB), alcohol and liver disease among injection drug users (IDUs) in Chennai, India and to inform future treatment initiatives and interventions to reduce the burden of liver disease in a population with a confluence of hepatotoxic factors. In the developed world, liver disease has emerged as a leading cause of morbidity among HIV-infected IDUs. However, little work has been done in developing countries which represent the fastest growing HIV epidemics among IDUs. HCV treatment is not widely available in the developing world; however this disparity will change raising the urgency of understanding how exposures unique to India affect prevalence and forms of liver disease and whether those at greatest risk can be identified with novel, culturally acceptable tools. Accordingly, our aims are: AIM 1: To ascertain the prevalence of fatty liver disease (e.g., steatosis, steatohepatitis) and investigate the hypothesis d4T use, HCV genotype 3, insulin resistance and alcohol use are independently associated; AIM 1.1: To validate existing diagnostic algorithms for steatosis and fibrosis and to compare the predictive accuracy of existing panels (e.g., APRI, FIB-4) with new panels that use low-cost tests and local risk factors; AIM 2: To determine whether steatosis and liver fibrosis impact the incidence of future hepatic adverse events associated with antiretroviral therapy (ART) and anti-tuberculosis therapy (ATT); AIM 3: To begin to pilot interventions to reduce the burden of liver disease among IDUs in India; AIM 3.1. To quantify the acceptability and potential for HCV treatment response (prevalence of single nucleotide polymorphisms [SNPs] in the IL28b gene) among IDUs in India; and AIM 3.2. To conduct a double-blinded placebo controlled randomized clinical trial to determine the efficacy of Vitamin E for the treatment of steatosis. We will achieve these aims through a mix of cross-sectional studies, longitudinal cohort follow-up and a double-blinded placebo controlled randomized clinical trial building on two existing cohorts. For Aim 1, we will use ultrasonography for steatosis and Fibroscan(R) for fibrosis. For Aim 2, we will follow persons semi-annually to identify new initiates of ART and ATT and conduct intensive follow-up after initiation to determine hepatic tolerability. In Aim 3, we will assess acceptability of HCV treatment via questionnaire and potential treatment response via host genetic testing. The Aim 3 trial will be conducted among 100 IDUs with histologic steatohepatitis at baseline. We have a small window of opportunity to prepare for the impending epidemic of liver disease among IDUs in the developing world. These findings will also inform donors such as PEPFAR and GFATM regarding treatment decisions as the prevalence of HIV-HCV co-infection continues to rise as a result of the increasing contribution of injection drug use to the HIV epidemic in the developing countries including Africa. PUBLIC HEALTH RELEVANCE: Injection drug users (IDUs) are at high risk for HIV and hepatitis infections and the long-term complications of these infections, including liver disease, drug-related hepatotoxicity and mortality. The findings from this study will help to inform interventions to reduce the morbidity and mortality associated with drug use, HIV and hepatitis C. to inform interventions to reduce the morbidity and mortality associated with drug use, HIV and hepatitis C.